Maternal methadone dose at delivery and neonatal abstinence syndrome

Maternal methadone dose at delivery and neonatal abstinence syndrome To the Editors: Seligman et al1 state that there is no relationship between maternal methadone dose at delivery and the development of neonatal abstinence syndrome. Their conclusion was based on high methadone doses used in their cohort and the arbitrary choice of dose group quartiles, which consequently masked a dose-effect relationship. We note that in their cohort, mothers received, on average, 117 mg/d (range, 20 to 340 mg) of methadone at delivery, which represents the upper scale of methadone prescribing. More recent reports have used more modest doses. Dryden et al used a median dose of 50 mg/d (range, 5 to 150 mg)2, Lim et al had an average of 97 mg/d (range, 15 to 240 mg),3 and in our own cohort we noted an average of 72 mg/d (range, 2.5 to 150 mg).4 We have identified a clear correlation between opiate dosing and withdrawal to the effect that with every 5-mg increase in methadone dosing, there was an increased risk of withdrawal of 17%. However, the dose-effect relationship of methadone significantly decreases in higher dose ranges. As lower average methadone doses are more frequently reported, the authors’ conclusion should be considered with caution.

Anthony J.W. Liu, MBBS, FRACP Ralph Nanan, Dr Med Habil, FRACP Discipline of Paediatrics Sydney Medical School–Nepean The University of Sydney Penrith, New South Wales, Australia 10.1016/j.jpeds.2010.08.047

References 1. Seligman NS, Almario CV, Hayes EJ, Dysart KC, Berghella V, Baxter JK. Relationship between maternal methadone dose at delivery and neonatal abstinence syndrome. J Pediatr 2010;157:428-33. 2. Dryden C, Young D, Hepburn M, Mactier H. Maternal methadone use in pregnancy: factors associated with the development of neonatal abstinence syndrome and implications for healthcare resources. BJOG: Int J Obstet Gynaecol 2009;116:665-71. 3. Lim S, Prasad MR, Samuels P, Gardner DK, Cordero L, Lim S, et al. Highdose methadone in pregnant women and its effect on duration of neonatal abstinence syndrome. Am J Obstet Gynecol 2009;200:70.e1-5. 4. Liu A, Jones M, Murray H, Cook C, Nanan R. Perinatal risk factors for the neonatal abstinence syndrome in infants born to women on methadone maintenance therapy. Aust N Z J Obstet Gynaecol 2010;50:253-8.

1970s. However, despite more than 30 years of experience, research methods remain largely proprietary and without agreed-upon standards. In our study, the lowest dose cohort was <80 mg/d, which represents the 25th percentile and is well within the range of 20 mg/day2 to 100 mg/day,3 used to define the lowest-dose cohort in other recent studies. In fact, most investigators follow this same approach of dividing the maternal methadone dose into cohorts2-6 rather than using logistic regression as used by Liu et al.1 Even following their method, methadone dose was not a significant predictor of neonatal withdrawal in our population, when controlled for gestational age at delivery and mode of delivery (P = .268). Despite significant overlap in methodology, it is unclear why our population does not exhibit the ‘‘doseeffect’’ relationship between maternal methadone dose and neonatal abstinence syndrome (NAS) demonstrated by Liu et al. Such a marked discrepancy in results may be due in part to variations in treatment practices and population characteristics (eg, potency of heroin and degree of abuse). A recent report from the Maternal Opioid Treatment Human Experimental Research (MOTHER) study showed significant differences in the characteristics of opioid-addicted pregnant women living in North America compared with those living in Central Europe7 suggesting that our two populations may not be totally comparable. An increased risk of NAS is a common concern of women when a change in methadone dose is suggested, despite the fact that a direct relationship has not been clearly established. Less than adequate maternal treatment may compromise some of the other neonatal benefits of methadone maintenance. Despite their conclusions about methadone dose and NAS, Liu et al demonstrated that neonates born to women on higher methadone doses had higher birth weight, were born later (38.4 versus 36.8 weeks), had a lower rate of growth restriction, and had a trend toward less maternal polydrug abuse (P = .06).6 We and others continue to support the use of methadone doses sufficient to abate maternal drug cravings, citing the maternal benefits (less illicit drug use), lack of association of NAS with maternal methadone dose, and the neonatal benefits.

Neil S. Seligman, MD Division of Maternal-Fetal Medicine Department of Obstetrics and Gynecology Jefferson Medical College Thomas Jefferson University Philadelphia, Pennsylvania

Reply To the Editors: We appreciate the interest in our report and are pleased to see the abundance of research on polysubstance abuse during pregnancy, by Liu et al.1 Methadone, for the management of opiate addiction, has been used during pregnancy since the 1044

10.1016/j.jpeds.2010.08.048

References 1. Liu A, Jones M, Murray H, Cook C, Nanan R. Perinatal risk factors for the neonatal abstinence syndrome in infants born to women on methadone maintenance therapy. Aust N Z J Obstet Gynaecol 2010;50:253-8.